Methylalkanoyloxymethyl ketals of prednisolone derivatives



United States Patent Int. Cl. C07c 173/00 U.S. Cl. 260239.55 4 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula:

wherein X is H or F and R is an alyl group having 3 to 5 carbon atoms possess anti-inflammatory action.

This invention relates to anti-inflammatory steroids, particularly prednisolone derivatives. It particularly relates to alkylalkanoyloxy alkyl ketals of fiuorinated prednisolone derivatives.

It is previously known to produce alkylalkanoyloxyalkyl ketals of prednisolone derivatives. These compounds have provide to have good anti-inflammatory effect, particularly when the alkanoyl group contains 1-2 carbon atoms. Tests with other acetals and ketals have shown that the number of carbon atoms in the acetal and ketal group should be low. Known methylalkanoyloxymethyl ketals are described in e.g. the British Pat. No. 1,020,309 and the Belgian Pat. No. 660,549.

Extensive research work has shown, quite surprisingly and contrary to the usual experiences with acetals and ketals of cortisone derivatives that a greater number of carbon atoms in the alkanoyl group of the ketal gives a considerably improved anti-inflammatory effect in relation to the anti-inflammatory effect obtained with ketals according to the above-mentioned patent. The number of carbon atoms in the alkanoyl group should then be at least 3 and not more than 5.

The compound according to the present invention has the following general formula:

in which R is an alkyl group which has at least 3 carbon atoms and not more than 5 cabon atoms, and in which X designates hydrogen or fluorine.

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An example is given of the production of one of the compounds according to the above-mentioned formula, and the other compounds are prepared in exactly the same way.

EXAMPLE 1 To a suspension of 300 mg. of triamcinolon in 7.5 ml. of dioxane (dried and newly distilled), 2.5 g. of caproyloxy-acetone and 25 mg. of perchloric acid are added. The reaction mixture is stirred at 20-30" C. in nitrogen gas atmosphere for 5 hours. Gradually, a homogeneous, acid solution is formed, which is neutralized with a 5% sodium bicarbonate solution to pH 6.5. The solution is extracted with chloroform, after which the chloroform layer is dried and evaporated in vacuum. The reaction is re-crystallized from approx. 10 ml. of a mixture of ethyl acetate and ligroin in the proportion 1:1. Triamcinolone caprolyoxyacetonide is obtained, with a yield of 82% and a melting point of 229-230 C.

The melting points of other compounds according to the foregoing general formula are given in the following table:

The anti-inflammatory effect of the substances according to Table 1 has been compared with triamcinolone acetyloxyacetonide according to the above-mentioned patents according to the granuloma test of adrenalectonized rats. This test was carried out on two series of animals. In one series, the corticosteroids according to Table 1 had been introduced in the animals subcutaneously, while the other series served as a reference. Thereafter, the increases in Weight of the used cotton pellets in the animals which had received the corticosteroids were compared With the animals which had not been treated with corticosteroids. A summary of the results of said tests is given in the following table:

TAB LE 2 Granulom weight in percent of granulom Daily weight of dose in Number reference No. Corticosteriod mg. of animals animals 1 Triameinolone acetyl- 10 48 69 oxyacetonide. 2 Triameinolone butyroyl- 10 8 67 oxyaeetonide. 3 Triameinolone valeroyl- 10 8 50 oxyacetonide. 4 Triamcinolone caproyl- 10 8 64 oxyacetonide. 5 Triamcinolone-3,3-di- 10 methyl-butyroyloxyacetonide. 6 Fluocinolone valeroyl- 10 8 62 oxyacetonide. 7 Triamcinolone acetyl- 3. 3 36 83 oxyacetonide. 8 Triarncinolone butyroyl- 3. 3 8 87 oxyacetonide. 9 Triamclnolone valeroyl- 3. 3 24 78 oxyacetonide. 10 Triamcinolone caproyl- 3. 3 16 82 oxyacetonide. 11 Triameinolone-3,3-di- 3. 3 8 99 methyl-bntyroyloxyacetonide. 12 Fluocinolone valeroyl- 3. 3 16 75 oxyaeetonlde.

From the above, it is clearly shown that the valeroyl- 4. A compound of the formula oxyacetonides have a considerably better anti-inflammatory effect compared with the other compounds. CHFOH We claim: H30 =0 1. A compound of the formula: 5 '-----O =0 0 cnr-o- -cim on 0 0/ cm-o-fi-m References Cited 15 UNITED STATES PATENTS 3,048,581 8/1962 Fried 260-23955 wherein R is an alkyl group containing from 4-5 car- 3,341,526 9/ 1967 Af Ekenstam 260-23955 bon atoms and X is hydrogen or fluorine.

2. A compound according to claim 1 wherein R is 20 LEWIS GOTTS Pnmary Examiner butyl. E. G. LOVE, Assistant Examiner 3. A compound according to claim 1 wherein R is amyl. US. Cl. X.R. 

